The overall goal of the proposed study is to examine the effects of acute nicotine deprivation on neurocognitive mechanisms of inhibitory self-regulation of behavior in chronic smokers and to determine whether these effects are moderated by dopamine-related genes. Tobacco use is recognized as the single most preventable cause of mortality and morbidity;however, the efficiency of smoking cessation treatment remains modest, primarily due to high rates of relapse within the first days of abstinence. Research suggests that nicotine deprivation can weaken inhibitory self-control of behavior, which may be a crucial factor contributing to relapse risk and susceptibility to nicotine dependence. However, little is known about neurocognitive mechanisms underlying nicotine deprivation-induced disinhibition and possible genetic influences on such effects. We hypothesize that nicotine deprivation affects prefrontal brain function underlying cognitive control and self-regulation of behavior, and that individual differences in susceptibility to these deprivation-induced deficits are influenced by specific dopamine-related genes. To test these hypotheses, we propose a controlled, human laboratory-based experimental study that will integrate cognitive neuroscience and pharmacogenomic methods to pursue the following Specific Aims: 1) to examine acute effects of nicotine deprivation on prefrontal event-related brain potentials (ERPs) and performance indicators of cognitive control, including response inhibition, action monitoring, and decision making and 2) to examine the effects of the catechol-O-methyltransferase (COMT) gene on individual differences in subjective, behavioral, and neurocognitive effects of smoking deprivation. To achieve these aims, we will: (i) genotype prospectively a group of chronic smokers (estimated n=140) for the COMT polymorphism and select three equal (n=30) genotype groups, (ii) conduct a single-blind, within-subject, crossover study, in which participants will be tested under deprived and non-deprived conditions in two separate laboratory sessions, and (iii) test for genotype by deprivation interaction effects on self-report, behavioral, and neurocognitive variables while controlling for important covariates. It is expected that this study will provide pilot and feasibility data for the development of a subsequent R01 application focusing on genetic and neurocognitive factors underlying smoking relapse. PUBLIC HEALTH RELEVANCE: Tobacco use is recognized as the single most preventable cause of death and disease in the United States, and many smokers attempt to quit every year. However, the efficacy of smoking cessation treatments remains modest, primarily due to the high rate of relapse to smoking within the first days of abstinence. Little is known about biological and behavioral factors underlying this failure of self-control and inability to resist smoking urges. A better understanding of the genetic and neurobiological factors contributing to smoking relapse can suggest new targets for behavioral and pharmacological treatment, which can ultimately lead to improved rates of successful quitting.